Draft monograph: GHRP-6 — submissions
The 11 submissions received, published in full with declared interests and secretariat responses.
§2Submissions and responses
11 submissions were received. Each is published in full below with its declared interest, the secretariat response and the disposition. The Institute publishes submissions it did not accept in the same form as those it did.
The document should state what a reader ought to do
The draft on GHRP-6 was read from the standpoint of a clinician asked about the compound by people already taking it.
The draft assesses evidence and stops. The respondent, a practising clinician, states that a reader arriving at the document with a decision to make is left to convert an assessment into an action without help, and proposes that each document close with a recommendation.
The respondent argues that other evidence bodies issue recommendations and that declining to do so transfers the difficult part of the work to the reader.
The secretariat does not accept this submission, and records that the point is a reasonable one rather than a misunderstanding.
The Institute assesses evidence and does not issue recommendations, because a recommendation embeds values and a resource context that the Institute does not hold and cannot state. That constitutional limit is published on the methodology page and is not varied by consultation. The submission remains published in full.
Regulatory status is stated without naming the jurisdiction
The respondent submits on the draft monograph for GHRP-6. Growth-hormone-axis compounds are supplied widely and studied narrowly, and a document about one should make that asymmetry visible.
The draft states that the compound is approved, or not approved, without saying by whom. The respondent, employed by a health-technology assessment body, states that approval status differs between jurisdictions for several compounds in the series and that an unqualified statement will be wrong somewhere.
The respondent proposes that every status statement name the authority and carry the date on which the status was checked.
The secretariat accepts this submission. An unattributed status statement is a claim the Institute cannot support.
Every regulatory status statement now names the authority, states the date on which the status was verified, and is recorded per jurisdiction rather than as a single global assertion.
The document is unreadable without specialist training
This submission concerns GHRP-6 and makes one point.
The respondent states that the draft is written for a reader who already understands certainty grading, and that the people most affected by the subject matter will not reach the assessment at all.
The respondent proposes a plain-language summary at the head of every document, written to the same standard of accuracy as the document itself and not as a promotional abstract.
The secretariat accepts this submission in part. A plain-language summary is added. The proposal that it replace the technical abstract is declined, because the abstract is the part of the document other assessors read and cite.
Every document now opens with a plain-language summary of not more than 150 words, placed above the technical abstract and carrying the same certainty language, so that the two cannot diverge.
Guidance on lyophilised storage is missing
The respondent notes that GHRP-6 is supplied for indications that no trial in the draft addresses, and submits in that context.
The respondent asks that the monograph state storage conditions for lyophilised material as well as for reconstituted solution, since the two differ and the former governs the longer part of the shelf life.
The respondent states that the omission is the more consequential because lyophilised material is what is generally received.
The secretariat notes this submission. The draft addresses lyophilised storage, in the presentation section rather than in the section on in-use handling, which is where the respondent looked.
No amendment to content arises. The two storage statements have been brought together under a single heading so that a reader looking for either finds both.
The analytical section assumes a reference standard that is not generally available
The respondent has read the draft covering GHRP-6 and makes one submission.
The draft describes identity and content determinations that require a reference standard of assigned content. For this compound no such standard is in general circulation, and a laboratory following the section as written cannot perform the determination described.
The respondent, employed by a contract analytical laboratory, proposes that the monograph state explicitly where a reference standard is unavailable and what a determination performed without one can still establish.
The secretariat accepts this submission. The section described an ideal case and did not say so.
The analytical section now states whether a reference standard is in general circulation for this compound and, where it is not, states which determinations remain possible and which become qualitative. A content figure obtained without a reference standard is recorded as an estimate against a stated assumption rather than as a determination.
Registered trials that never reported are absent from the monograph
The respondent read the draft on GHRP-6 and has confined this submission to a single matter.
The respondent states that the trial list appears to be drawn from published reports, and that registered trials which completed without a report are therefore invisible. The proportion of a programme that never reported is itself a finding about the evidence base.
The respondent proposes that every registered trial of the compound be listed, with its reporting status, whether or not a report exists.
The secretariat accepts this submission. A trial list built from publications reproduces publication bias in the shape of the document.
The trial list now includes every registered trial the Institute identified, with its reporting status stated, and the monograph reports the proportion of registered trials for which no result has been posted or published.
The same concept is given three different names in one document
The respondent’s comment on the draft for GHRP-6 arises from the anti-doping literature, in which this class is well represented and clinically it is not.
The draft refers to the same quantity as a response rate, a responder proportion and a categorical outcome in different sections. The respondent, who works in health-technology assessment, states that a reader cannot tell whether the three refer to one thing or to three.
The respondent proposes that the glossary term be used at every occurrence and that the glossary entry be linked at first use in each section rather than only at first use in the document.
The secretariat accepts this submission. The variation was stylistic and its cost to the reader exceeds any benefit.
A single term is now used throughout for each defined concept, and the glossary entry is linked at first use within each section rather than once per document.
The recorded evidence gaps omit outcomes a reader would consider material
This submission concerns the draft on GHRP-6. The respondent works in an endocrine service in which compounds of this class are assessed.
The evidence-gap section records what has not been studied. The respondent, a practising clinician, states that the list is drawn from the outcomes the trials chose to measure and therefore reproduces the sponsor's outcome selection rather than correcting for it.
The respondent proposes that the gap list be constructed from the outcomes a prescribing decision turns on, and that outcomes measured by no trial appear in it as such.
The respondent notes submission 007 above and does not repeat the ground it covers.
The secretariat accepts this submission in part. The gap list is reconstructed from the decision-relevant outcome set rather than from the measured set. The proposal that every unmeasured outcome be listed is declined, because an unbounded list of things not studied is not a finding.
The evidence-gap section is now derived from the anchor and decision-relevant outcomes for the indication, and any such outcome measured by no contributing trial is recorded as not measured rather than omitted.
The supply section does not record that endotoxin is not determined
The respondent submits on GHRP-6.
The compound is supplied as a lyophilisate intended for reconstitution and injection. The supply section lists the determinations that certificates carry and does not state that endotoxin is not among them, which is the determination whose absence has the most direct consequence for that presentation.
The respondent proposes an explicit line in §8 for every compound supplied in an injectable presentation, stating whether endotoxin is determined and, where it is not, what that means.
The secretariat accepts this submission. The omission was an artefact of listing what is present rather than what is absent.
Section 8 now carries an explicit endotoxin line for every compound supplied in an injectable presentation, and states plainly that an undetermined attribute is undetermined rather than acceptable.
The mechanism section is written with more confidence than the clinical section it precedes
This submission concerns the draft on GHRP-6 and is made from an endocrine standpoint.
The pharmacology section states what the compound does at its receptor in the indicative mood and without hedging. The clinical section then reports that the effect has not been demonstrated in people. A reader who stops after the first section, as many will, takes away a claim the document goes on to withdraw.
The respondent does not propose that the pharmacology be hedged, which would be inaccurate, but that each pharmacology section close with a sentence stating which of the described actions has been shown to produce a clinical effect and which has not.
The respondent’s submission overlaps with submission 007 and was prepared without sight of it.
The secretariat accepts the proposal in part. Receptor pharmacology is often well established and hedging it would misdescribe the literature.
Every pharmacology section now closes with a statement identifying which described actions are supported by clinical evidence assessed in §3 and which are not. The pharmacology itself is stated as the sources state it.
The route of administration studied is not the route in which the compound is supplied
Having read the draft monograph on GHRP-6, the respondent puts one point to the committee.
The clinical section describes findings obtained by one route and the supply section describes presentations intended for another. A reader moving between the two sections will carry the effect estimate across the change without noticing that it has been carried, because nothing on the page marks the transition.
The respondent proposes that where the studied route and the supplied presentation differ, the difference be stated in the assessed-outcome table itself rather than in the supply section, on the ground that a reader consults the outcome table and does not always reach §8.
The secretariat accepts this submission. The route by which an estimate was generated is a condition of the estimate and belongs beside it.
The assessed-outcome table now carries the studied route in every row, and a standing note appears wherever the supplied presentation differs from it.
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- International Organization for Standardization. ISO/IEC 17025:2017 General Requirements for the Competence of Testing and Calibration Laboratories. ISO/IEC Standard 2017;3rd edition. identifier not held by the Institute
Identifiers are reproduced only where the Institute holds them. Where a digital object identifier or PubMed identifier is not shown, the Institute has recorded the journal and year and has not constructed an identifier.